The long-term objective for this proposal is the elucidation of molecular mechanisms for the wingless-type (Wnt)/beta-catenin signaling pathway in malignant mesothelioma (MM) and the development of molecular therapies for this malignancy. Mesothelioma is a relatively uncommon but inexorably fatal tumor, affecting about 3000 new patients in the United States annually. Despite advances in cancer treatment, the medium survival rate remains low and most patients die within two years after diagnosis. The pathogenesis of mesothelioma remains poorly understood and the molecular mechanism by which mesothelial cells undergo neoplastic transformation is largely unknown. For this proposal, we will test the hypothesis that aberrant activation of Wnt signaling pathway plays important roles in malignant mesothelioma. Preliminary data from our laboratory showed that the Wnt signaling pathway is activated in MM as evidenced by increased cytosolic/nuclear beta-catenin, and c-Myc, the two downstream target genes, downregulation of the potential endogenous inhibitor secreted frizzled related protein (SFRP2), and an increased phosphorylation of the Wnt pathway mediator dishevelled protein (Dvl-3). These observations have not been described previously nor elucidated in MM. The specific Aims for this application are 1) to confirm that Wnt signaling pathway is activated in mesothelioma in a large number of primary tumor samples: 2) to investigate molecular mechanisms of Wnt signaling activation in mesothelioma. initially by examining the role of SFRP2 and Dvl-3; 3) to investigate whether a Wnt-1 signaling is a survival factor, thus inhibits apoptosis, in mesothelioma using an anti-Wnt-1 ligand monoclonal antibody and siRNA; and 4) to develop molecular therapies by targeting the Wnt-1 ligand with monoclonal antibody in vivo. Recent information about the Wnt signaling pathway reveals its vital importance in both embryogenesis and oncogenesis. Our study aims to reveals its role in malignant mesothelioma, and to add significantly to the emerging knowledge about the Wnt pathway in cancer in general.